Through an integrated program of basic and clinical studies, we shall continue to examine the effects of opiates and amphetamines on catecholamine metabolism, and to explore the role of catecholamines in the reinforcing properties of these drugs and in the biochemical pathophysiology of opiate and amphetamine addictions. In our clinical study of heroin self-administration, we have obtained evidence of anticipatory or conditioned increases in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine in the brain, occuring on the day before heroin availability, and our preliminary findings indicate that both the morphine-induced and amphetamine-induced increases in levels of MHPG in rat brain can be conditioned. This application proposes: 1) to develop and refine the experimental conditions that will enable us to obtain morphine- and amphetamine-induced conditioned increases in MHPG levels in rat brain with the consistency needed for further research using this paradigm; 2) to study the effects of opiates and amphetamines on thresholds of intracranial reinforcement; 3) to study the amphetamine-withdrawal state in rats (which is associated with decreases in brain levels of MHPG and increases in thresholds of reinforcement) as a possible animal model of one type of depressive disorder encountered clinically; and 4) to complete statistical analyses of the data on urinary catecholamines and metabolites obtained during our study of heroin self-administration in man.